Charcot-Marie-Tooth (CMT) neuropathy, also known as hereditary motor and sensory neuropathy, is a heterogeneous group of inherited diseases of peripheral nerves. CMT is a common disorder affecting both children and adults, and causing significant neuromuscular impairment. It is estimated that 1/2500 persons have a form of CMT, making it one of the largest categories of genetic diseases.
CMT is traditionally classified by whether the primary pathological defect is degeneration of myelin (CMT1) or of axons (CMT2) in the peripheral nerves. CMT1 is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A mutations are associated with the gene for peripheral myelin protein 22 (PMP22); CMT1B mutations are associated with myelin protein P zero (P.sub.0) ; and CMTX mutations are associated with the connexin-32 gene (C.times.32). Connexin-32 is a 32-kilodalton protein, located at uncompacted folds of schwann cell cytoplasm around the nodes of Ranvier and at Schmidt-Lanterman incisures. This localization suggests a role for gap junctions composed of connexin-32 in providing a pathway for the transfer of ions and nutrients across and around the myelin sheath.
The clinical features of CMTX include demyelinating neuropathy characterized by progressive distal extremity weakness, atrophy, sensory loss, and areflexia; absence of male-to-male transmission; and a generally earlier onset and faster rate of progression of illness in males. Distinguishing between CMT1A and CMTX based on clinical and family history, or results from motor nerve conduction velocity (NCV) testing, is extremely difficult. Complicating the clinical diagnosis further is the high rate of affected female carriers of the CMTX mutations: the CMTX family pedigrees therefore do not demonstrate an X-linked transmission pattern. CMTX may be present in any families without male-to-male transmission of the disease. Methods to distinguish CMTX from other forms of CMT disease are necessary to facilitate disease diagnosis and treatment.